This proposal is to study the actions of antitumor bis-guanylhydrazones on the metabolism and functions of polyamines, as related to the chemotherapeutic activity and toxicity of the drug, on the one hand and the role of polyamines in cell division on the other hand. Methylglyoxal-bis(guanylhydrazone) will be studied as an example of a specific inhibitor of spermidine synthesis with antileukemic activity in humans. The objectives of this investigation are 1) to clarify the pharmacological and molecular basis for the cytotoxicity of methylglyoxal-bis(guanylhydrazone) in tumor and normal-proliferating as well as non-proliferating tissues; 2) to assess the importance of physiological polyamines as targets for cancer chemotherapy, and to develop a suitable model to carry out such studies; 3) to obtain information on structure-activity relationship among bis-guanylhydrazones with reference to their effects on polyamine metabolism and functions; and 4) to utilize the information obtained to improve the selective toxicity of methylglyoxal-bis(guanylhydrazone). Most of the work will be performed in inbred mice with syngeneic leukemia. Among the methods involved will be those used for the separation of different polyamines and their precursors, for the estimation of their pools and of the enzymic activities involved in turnover of polyamine pools. Correlations will be drawn between drug kinetics, polyamine metabolism and functional impairment of metabolism for cytotoxicity in normal and tumor tissues. Attempts will be made to develop a pharmacokinetic model in mice for optimizing drug regimen. It is expected that such information will be applicable in attempts to reduce the toxicity of the drug in humans. BIBLIOGRAPHIC REFERENCES: C. Dave and R. Bernacki, Studies on the Role of n-Acetylneuraminic Acid (NANA) on the Uptake of Spermidine in Mouse Leukemia L1210 Cells. Proc. Amer. Assoc. Cancer Res. 16, 73, 1975. C. Dave and Y.C. Cheng, Effect of Methylglyoxal-bis(guanylhydrazone) on the Activities of Ornithine and s-Adenosylmethinine Decarboxylases in HeLa Cells. The Pharmacologist 17, 230, 1975.